Glucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages.

TitleGlucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages.
Publication TypeJournal Article
Year of Publication2017
AuthorsRollins DA, Kharlyngdoh JB, Coppo M, Tharmalingam B, Mimouna S, Guo Z, Sacta MA, Pufall MA, Fisher RP, Hu X, Chinenov Y, Rogatsky I
JournalNat Commun
Volume8
Issue1
Pagination1739
Date Published2017 Nov 23
ISSN2041-1723
Abstract

The glucocorticoid (GC) receptor (GR) suppresses inflammation by activating anti-inflammatory and repressing pro-inflammatory genes. GR-interacting protein-1 (GRIP1) is a GR corepressor in macrophages, however, whether GRIP1 mediates GR-activated transcription, and what dictates its coactivator versus corepressor properties is unknown. Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator. Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. Consistently, phospho-GRIP1 and CDK9 are not detected at GR transrepression sites near pro-inflammatory genes. Thus, GR restricts actions of its own coregulator via CDK9-mediated phosphorylation to a subset of anti-inflammatory genes.

DOI10.1038/s41467-017-01569-2
Alternate JournalNat Commun
PubMed ID29170386
PubMed Central IDPMC5700924
Grant ListR00 CA149088 / CA / NCI NIH HHS / United States
P30 CA086862 / CA / NCI NIH HHS / United States
R01 DK099087 / DK / NIDDK NIH HHS / United States
T32 AR007281 / AR / NIAMS NIH HHS / United States
R01 GM104291 / GM / NIGMS NIH HHS / United States
K99 CA149088 / CA / NCI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States

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